Cancer Vaccine Passes Early Test in Melanoma

Action Points

A vaccine that stimulated durable immune responses in a small study of melanoma patients suggests new strategies to boost T-cell immunity in cancer patients.

Note that the vaccine consists of the patients' own dendritic cells, modified to produce interleukin-12p70 (IL-12p70), a protein involved in differentiation of T cells into the cytotoxic Tc1 phenotype.

A vaccine that stimulated durable immune responses in six of seven melanoma patients suggests new strategies to boost T-cell immunity in cancer patients, investigators reported.

Three of the six patients had confirmed clinical responses, including one patient who remained in complete remission more than 4 years.

The vaccine consists of the patient's own dendritic cells, modified to produce interleukin-12p70 (IL-12p70), a protein involved in differentiation of T cells into the cytotoxic Tc1 phenotype. Previous studies showed that IL-12p70 has clinical activity in cancer patients but proved too toxic to incorporate directly into vaccine formulations.

The lack of clinical response in four patients was traced to a transcription defect in the dendritic cells, which has since been corrected, Beatriz M. Carreno, PhD, of Washington University in St. Louis, and co-authors reported online in the Journal of Clinical Investigation.

"These results highlight the critical role of IL-12p70 in developing CD8+ T-cell immunity and the potential value of this cytokine as a surrogate for vaccine efficacy and also suggest new strategies to enhance T-cell immunity in patients with cancer."

Experimental evidence has suggested a role for IL-12p70 as a vaccine adjuvant. Current dendritic cell-based vaccine formulations fail to incorporate CD40/TLR/IFNR signaling (necessary for production of bioactive IL-12p70) during maturation. As a result, the anticancer potential of mature, IL-12p70-producing dendritic cells remained unclear.

Carreno and colleagues hypothesized that immunization with functionally mature, IL-12p70-producing dendritic cells would lead to antigen-specific immunity and clinical activity in patients with advanced cancer.

Using the matured dendritic cells, the team immunized seven patients with untreated stage IV melanoma against the gp100 melanoma antigen. All of the patients had biopsy- and histology-proven gp100-positive metastatic melanoma.

After receiving a single dose of cyclophosphamide, the seven patients received six doses of the vaccine, administered at three-week intervals. Vaccination led to a significant increase in gp100-specific T-cell immunity against all three melanoma gp100 antigen-derived peptides. Levels of vaccine-derived IL-12p70 correlated significantly with time to progression (P=0.019).

The three objective clinical responses observed during the study persisted for durations of 352 to 1,416 days.

On the basis of the immunologic response, two doses of vaccine probably would be sufficient to achieve induction of high-avidity T cells to native gp100 protein in most patients, the authors stated.

When the investigators analyzed gp100-specific T cells from patients who did not achieve a clinical response, they identified a pathway-specific defect in IL-12p35 transcription in the activation protocol for the dendritic cells, resulting in gp100-specific T cells with a Tc2 phenotype.

Incorporation of toll-like receptor (TLR) 3 and TLR8 agonists corrected the production defect, as indicated by the presence of gp100-specific T cells with the Tc1 phenotype.

The study was supported by the Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Washington University/JNJ Translational Medicine Award, and the National Cancer Institute.

Carreno reported no relevant disclosures. Co-authors include an employee of EMD Millipore, a division of Merck KGaA of Germany.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

POPULAR IN YOUR SPECIALTY

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.